Abstract
Abstract Senescence is a cell cycle arrest program that limits the expansion of damaged cells and can trigger antitumor immunity that leads to their elimination in vivo, serving as a potent barrier to tumorigenesis. However, during tumor initiation, the effective clearance of senescent cells is compromised, warranting a deeper mechanistic understanding of this process. To define the critical immunomodulatory factors mediating senescence immune surveillance and how these mechanisms are bypassed during cancer development and progression, we exploited a genetic approach in which liver tumor cells can be triggered to senesce by restoration of tumor suppressor p53. p53 reactivation triggers cytostatic response in vitro, yet it drives robust regression of established liver tumors in immunocompetent mice. Profiling of the immune landscape upon senescence induction revealed that there is an accumulation of CD8 and CD4 T cells in the tumor microenvironment. Consistently, immune cell blockade through depleting antibodies blunts tumor regression, indicating a key role of adaptive immunity in this process. To gain mechanistic insight into how senescent cells are recognized by the immune system, RNA-seq and mass spectrometry were conducted on both proliferating and senescent tumor cells and revealed several senescence-enriched cell surface factors related to epithelial-immune cell interactions and MHC-I presentation. Ongoing work aims to functionally interrogate the role of these senescence-induced factors as novel senescence surveillance effectors. Our research will increase the current knowledge of the strategies to trigger senescence in advanced cancers that can restore immune surveillance programs lost during the course of tumor evolution. Citation Format: Hsuan-An Chen, Direna Alonso-Curbelo, Yu-Jui Ho, John P. Morris IV, Shauna Houlihan, Ryan Smolkin, Wei Luan, Ronald C. Hendrickson, Scott W. Lowe. Dissecting the mechanisms of senescence immune surveillance in liver cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A29.
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